This U.S. non-provisional application claims priority under 35 U.S.C. §119 to Korean Patent Application No. 2002-46551, filed on Aug. 7, 2002, in the Korean Intellectual Property Office, the contents of which are incorporated herein by reference in its entirety.
1. Field of the Invention
The present invention relates to a 1,2,4-triazole derivative or non-toxic salt thereof, a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient.
2. Description of the Related Art
Most nonsteroidal antiinflammatory agents are responsible for blocking the enzyme, cyclooxygenase (COX) or prostaglandin G/H synthase, thereby reducing inflammation, pain, or fever. In addition, they inhibit uterus contraction caused by hormones and also inhibit growth of several cancers. Cyclooxygenase-1 (COX-1) was first discovered in bovine. The COX-1 is constitutively expressed in a variety of cell types. Unlike the COX-1, cyclooxygenase-2 (COX-2) is a recently discovered isoform of cyclooxygenase that is easily inducible by mitogen, endotoxin, hormone, growth factor, or cytokine.
Prostaglandin is a potent mediator of various pathological and physiological processes. The COX-1 plays important physiological roles such as the release of endogenous prostaglandin, the maintenance of the shape, the function of stomach, and blood circulation in kidney. On the other hand, the COX-2 is induced by an inflammatory factor, hormone, growth factor, or cytokine. Therefore, the COX-2 is involved in pathological processes of prostaglandin unlike the constitutive COX-1.
In this regard, selective inhibitors of the COX-2 produce fewer and less side effects in terms of action mechanism in comparison with conventional nonsteroidal antiinflammatory agents. In addition, they reduce inflammation, pain, and fever and inhibit uterus contraction caused by hormones and growth of several cancers. In particular, they are effective in decreasing side effects such as stomach toxicity and kidney toxicity. Still furthermore, they inhibit the synthesis of contractile prostanoid, thereby leading to suppression of the contraction of smooth muscles. Therefore, premature birth, menstrual irregularity, asthma, and eosinophilic disease can be prevented.
Recently, it was reported that nonsteroidal antiinflammatory agents are effective in treating large intestine cancer [European Journal of Cancer, Vol 37, p 2302, 2001], prostate cancer [Urology, Vol 58, p 127, 2001], and dementia [Exp. Opin. Invest. Drugs, Vol 9, p 671, 2000].
In addition, it is anticipated that selective COX-2 inhibitors would be effective in treating osteoporosis and glaucoma. Utility of selective COX-2 inhibitors is well described in documents [John Vane, “Towards a Better Aspirin” in Nature, Vol. 367, pp 215–216, 1994; Bruno Battistini, Regina Botting and Y. S. Bakhle, “COX-1 and COX-2: Toward the Development of More Selective NSAIDs” in Drug News and Perspectives, Vol. 7, pp 501–512, 1994; David B. Reitz and Karen Seibert, “Selective Cyclooxygenase Inhibitors” in Annual Reports in Medicinal Chemistry, James A. Bristol, Editor, Vol. 30, pp 179–188, 1995].
Various selective COX-2 inhibitors having different structures have been known. Among them, a selective COX-2 inhibitor having a diaryl heterocyclic structure, i.e. a tricyclic structure has been widely studied as a potent candidate. The diaryl heterocyclic structure has a central ring and a sulfonamide or methylsulfone group attached to one of the aryl rings. An initial substance having such diaryl heterocyclic structure is Dup697 [Bioorganic & Medicinal Chemistry Letters, Vol 5, p 2123, 1995]. Since then, SC-58635 having a pyrazol ring (Journal of Medicinal Chemistry, Vol 40, p 1347, 1997) and MK-966 having a furanone ring (WO 95/00501) were discovered as derivatives of the Dup697.
One selective COX-2 inhibitor, Celecoxib of formula 58 is disclosed in U.S. Pat. No. 5,466,823. The Celecoxib is a substituted pyrazolyl benzenesulfonamide derivative. 
Another selective COX-2 inhibitor, Rofecoxib of formula 59 is disclosed in WO 95/00501. The Rofecoxib has a diaryl heterocyclic structure with a central furanone ring. 
Valdecoxib of formula 60 as another selective COX-2 inhibitor is disclosed in U.S. Pat. No. 5,633,272. The Valdecoxib has a phenylsulfonamide moiety with a central isoxazole ring. 
The selective COX-2 inhibitors of formulas 58 to 60 are effective inflammatory therapeutic agents with fewer and less side effects in comparison with conventional nonsteroidal antiinflammatory agents.